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ARE STRATIFICATION EFFECTS REAL? A CASE STUDY FROM THE ALCOHOL FIELD

This case study explores the effects of genes related to alcohol metabolism on alcohol dependence risk and consumption levels, specifically in Japanese populations. The study examines the ALDH and ADH2 loci and their association with alcohol-related phenotypes. The study also investigates potential stratification effects in diverse populations.

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ARE STRATIFICATION EFFECTS REAL? A CASE STUDY FROM THE ALCOHOL FIELD

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  1. ARE STRATIFICATION EFFECTS REAL? A CASE STUDY FROM THE ALCOHOL FIELD Andrew C. Heath, D.Phil. Washington University School of Medicine St. Louis, Missouri

  2. ALCOHOL METABOLISM Alcohol Dehydrogenase (ADH) Aldehyde Dehydrogenase (ALDH) ALCOHOL ACETALDEHYDE ACETATE

  3. Asian Studies of Japanese Alcoholics and Controls Work by Higuchi, Murumatsu and colleagues is documenting ways in which genes that influence alcohol metabolism may be associated with differences in alcohol dependence risk or alcohol consumption levels. (Higuchi et al., 1994) (Murumatsu et al., 1996)

  4. Higuchi Data -- Japanese Alcoholics and Controls: ALDH2 locus Controls Alcoholics (N=461) (N=655) Locus Genotype (%) (%) ALDH2 *1 / *1 58 88 *1 / *2 35 12 *2 / *2 7 0 p < .001 (Higuchi, 1994)

  5. Higuchi Data -- Japanese Alcoholics and Controls: ADH2 locus (in those who are ALDH2*1/*1 homozygotes) Population Controls Alcoholics ADH2 *1 / *1 7.3% 30.4% *2 / *1 34.7% 33.7% *2 / *2 58.1% 35.8% From Higuchi’s community data, in individuals who are also ALDH2*1/*1 homozygotes, we may estimate the penetrance of the AHD2*2/*2 genotype (the low risk genotype) as 7%, that of the high risk ADH2*1/*1 genotype as 29%.

  6. Higuchi Data -- Genetic effects on alcohol consumption levels in a community sample Average monthly alcohol consumption (ml pure alcohol) Genotype MEN ALDH2*1/*1 1054.7 ALDH2*1/*2 390.9 ALDH2*2/*2 94.1 From other data, we can estimate that approximately ONE-THIRD of the variance in alcohol consumption levels in males is explained by this genetic locus. No significant effects of the ADH2 locus were observed. (Higuchi et al., 1996b)

  7. Higuchi -- Temporal Changes in ALDH2*1/*2 Frequency in Japanese Alcoholics 1979 1986 1992 (N=400) (N=400) (N=500) (%) (%) (%) ALDH2 *1 / *1 97.5 92.0 87.0 *1 / *2 2.5 8.0*** 13.0** *2 / *2 0.0 0.0 0.0 i.e. GENOTYPE X ENVIRONMENT INTERACTION? Protective effect of a single *2 allele is being diminished in more recent cohorts. (Higuchi, 1994)

  8. FREQUENCIES OF GENES INFLUENCING ALCOHOL METABOLISM High Risk Japanese European Locus Allele AncestryAncestry ALDH2 ALDH2*1 76% 100% ADH2 ADH2*1 25% 95% ADH3 ADH3*2 6% 45% NOTE: Predicted magnitude of effects is ALDH2*1 >> ADH2*1 >> ADH3*2.

  9. CAN WE DEMONSTRATE SIGNIFICANT PROTECTIVE EFFECT OF THE ADH2*2 ALLELE IN INDIVIDUALS OF EUROPEAN ANCESTRY?

  10. Lifetime DSM-III-R Alcohol Dependence by ADH2 Genotype at Follow-up of the Australian Alcohol Challenge Twin Study Sample Whitfield et al., 1998

  11. QUANTITATIVE INDICES of ALCOHOL CONSUMPTION and PROBLEMS IC-1Weekly drinks in 1979-81 IC-2Average weekly consumption in 1979-81 FC-1Consumption in past week, 1990-91 FC-2Average weekly consumption in 1990-91 FC-3Weekly drinks in 1990-91 SC-1Average weekly consumption in 1992-94 FD-1Symptom count in 1990-91 SD-1Symptom count in 1992-94 (Whitfield et al., 1992)

  12. QUANTITATIVE INDICES of ALCOHOL CONSUMPTION and PROBLEMS (Whitfield et al., 1998)

  13. SURGEON GENERAL’S WARNING Using standard case-control comparisons to test for genetic association due to linkage disequilibrium can be dangerous! Danger of false positive findings in populations of diverse ancestry, e.g. most nations except population isolates, or possibly Finland, or Japan. Findings for the DRD2 ‘A1’ allele may be an example of this.

  14. POPULATION STRATIFICATION Hypothetical Example NORTHERN EUROPEAN ANCESTRY (N=200) SOUTHERN EUROPEAN ANCESTRY (N=200) NOT ROMAN CATHOLIC ROMAN CATHOLIC NOT ROMAN CATHOLIC ROMAN CATHOLIC 35 15 25% 105 45 75% 70% 30% 162 18 90% 18 2 10% 90% 10% NOT A1 allele A1 allele NO ASSOCIATION NO ASSOCIATION MINGLED IN AUSTRALIAN POPULATION (N=400) NOT ROMAN CATHOLIC ROMAN CATHOLIC NOT A1 allele A1 allele 197 33 123 47 OR = 2.28, 95%CI 1.39 - 3.73 Falsely infer that A1 allele is risk-factor for Roman Catholicism.

  15. SOCIOCULTURAL CORRELATES of ADH2*12 GENOTYPE in the AUSTRALIAN TWIN PANEL (I) Respondent Religious Affiliation: OR 95% CI Church of England 2.35 1.14-4.85 Any other 1.00 --- Parental Religious Affiliation: Both parents COE 3.36 1.14 - 9.94 Single parent COE 2.00NS 0.59 - 6.82 Neither parent COE 1.00 ---

  16. 1981 SURVEY SOCIAL ATTITUDES MEN ADH2*11 ADH2*12 OR 95% CI Socialism 40.2% 81.8% 6.68 1.36 - 32.91

  17. SOCIOCULTURAL CORRELATES OF ADH2*12 GENOTYPE (II) 1981 Survey Social Attitudes WOMEN (Does respondent agree or disagree with . . .) ADH2*11 ADH2*12 OR 95% CI Working mothers 25.0% 75.0% 10.93 2.09 - 57.14 Pyjama parties 27.5% 85.7% 15.83 1.84 - 136.13

  18. CONCLUSIONS For phenotypes which show considerable variation in prevalence between different ancestral groups, the danger of artifactual findings is real – but, as we have discussed this week and will discuss more this session, there are also good methods for addressing these problems.

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